The only immunologic mechanism that completely blocks host infection is recognition of the invading pathogen by specific antibody. Thus, an ideal vaccine is one that induces long-liver production of such neutralizing antibodies. This proposal is designed to develop strategies that enhance and prolong the humoral immune response to neutralizing epitopes on infectious pathogens through targeted delivery of foreign antigens to murine complement receptor type 2 (CR2; CD21). Interaction of foreign antigen with murine CR2 is critical for the primary humoral immune response to both T-dependent and T-independent antigens, as well s for the induction of immunologic memory. This immunomodulatory effect is thought to result from interaction of antigen bearing C3 complement ligands with the CR2-CD19 membrane complex on B lymphocytes and/or via localization and persistence of such antigens upon delivery to CR2 expressed on follicular dendritic cells. These observations suggest that targeted delivery of immunogens to CR2 will enhance both the primary as eell as the anamnestic response during vaccination. This hypothesis will be explored through studies of influenza virus which has been chosen for several reasons. influenza is a significant human pathogen, particularly among infants and the elderly population, and current vaccines are only partially effective. Antibodies specific for the viral surface glycoprotein hemaggglutinin (HA) are the primary defense against influenza infection, and the neutralizing epitopes on HA have been well defined. Furthermore, viral strains are available that have been adapted for pathogenicity in mice, and the murine immune response to influenza has been well characterized. The experimental approach will involve immunization of mice with C3-HA fusion proteins or C3-bearing influenza virus which should be targeted to both lymphocytes and follicular dendritic cells (FDC). The protective effect during in vivo challenge with influenza will be compared with a traditional influenza vaccine as well as with other novel influenza vaccines described in this proposal. It will also be determined whether modulation of the immune response to influenza by immunization with C3-HA is mediated via CR2 expressed on lymphocytes and/or on FDC through similar studies in RAG-2 deficient mice that have been reconstituted with either normal embryonic stem cells such that they express complement receptors on both lymphocytes and FDC or with embryonic stem cells that have been rendered complement receptor deficient through gene targeting, such that they express CR2 only on FDC.